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EMR combined with chemoradiotherapy: a novel treatment for superficial esophageal squamous-cell carcinoma
EMR combined with chemoradiotherapy: a novel treatment for superficial esophageal squamous-cell carcinoma Yuichi Shimizu, MD, Mototsugu Kato, MD, Junji Yamamoto, MD, Souichi Nakagawa, MD, Hiroyuki Tsukagoshi, MD, Masahiro Fujita, MD, Masao Hosokawa, MD, Masahiro Asaka, MD Sapporo, Japan
Background: Esophagectomy or chemoradiotherapy (CRT) are the procedures of choice for patients with superficial esophageal squamous-cell carcinoma. However, esophagectomy is highly invasive, and CRT is associated with the risk of local failure. A study was conducted of a novel treatment, EMR combined with CRT, for patients with superficial esophageal carcinoma. EMR was performed for the purpose of complete local tumor control and chemoradiotherapy was performed for regional and distant control. Methods: EMR combined with CRT was performed for patients with esophageal carcinoma invading the muscularis mucosae or upper submucosa who refused esophagectomy. The planned treatment after EMR was 40 to 46 Gy of external beam radiation to the mediastinum, including the supraclavicular fossa or cardia. Chemotherapy was given during weeks 1 and 5 (5-fluorouracil, 700 mg/m2 per 24 hours in a 120-hour infusion, and cisplatin 15 mg/m2 per day intravenously on days 1 to 5). Results: During the study period, 16 patients underwent EMR combined with CRT (EMR plus CRT group) and 39 patients with similar stage cancer underwent esophagectomy (surgical resection group). None of the patients in the EMR plus CRT group have had local recurrence or metastasis. Overall survival rates at 5 years in the EMR plus CRT and surgical resection groups were estimated to be, respectively, 100% and 87.5%. Conclusions: Although this study was not randomized, the results suggest that EMR combined with CRT is a safe and effective method for treating patients with superficial esophageal carcinoma. The results were equivalent or, in view of the lower degree of invasiveness, superior to surgical resection. (Gastrointest Endosc 2004;59:199-204.)
Because of the development of endoscopic methods of diagnosis, the frequency of superficial esophageal carcinoma, i.e., esophageal carcinoma that has not invaded beyond the submucosa (T1; International Union Against Cancer, 1997) has increased relative to the frequency of esophageal squamous-cell carcinoma of all stages. Subtotal esophagectomy with lymph node dissection is the treatment of choice for patients with superficial esophageal carcinoma invading the muscularis mucosae or deeper histologic layers because lymph node metastasis often occurs with such tumors.1,2 However, esophagectomy is highly invasive and associated with increased morReceived June 16, 2003. For revision September 4, 2003. Accepted November 4, 2003. Current affiliations: Division of Endoscopy, Hokkaido University Medical Hospital, Sapporo, Japan, Department of Internal Medicine, Department of Pathology, Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan, Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan. Reprint requests: Yuichi Shimizu, MD, Division of Endoscopy, Hokkaido University Medical Hospital, Kita 15 jo Nishi 7, chome, Kitaku, Sapporo 060-8638, Japan. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(03)02688-9 VOLUME 59, NO. 2, 2004
bidity and mortality.2 Chemoradiotherapy (CRT) is an alternative treatment for patients with superficial esophageal carcinoma. Many studies have demonstrated the effectiveness of CRT for patients with esophageal squamous-cell carcinoma.3-8 The Radiation Therapy Oncology Group in North America (RTOG) reported a complete response rate of 74% in 49 patients with stage II-III esophageal carcinoma who underwent CRT.6 Nevertheless, local failure often occurs in patients who have undergone CRT, and local tumor control remains the biggest problem. In the RTOG study, the final local cancer persistence or recurrence rate was 63%.6 EMR increasingly is being used to treat early stage esophageal carcinoma because it is minimally invasive and benefits patients in terms of quality of life (QOL).9-12 EMR currently is recommended for tumors confined to the lamina propria of the mucosa, which are known to have no risk of lymph node metastasis.2,9-12 However, it is possible to completely remove tumors invading the upper third to upper half of the submucosa by using EMR techniques.9,11 Because of the completeness of local tumor control, EMR is regarded by us as the best procedure for patients with superficial carcinoma, except for those with tumors invading the deep submucosa. GASTROINTESTINAL ENDOSCOPY
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Esophageal squamous-cell carcinoma: EMR combined with chemoradiotherpy
This study prospectively evaluates the long-term outcome after EMR combined with CRT in patients with squamous-cell carcinoma of the esophagus invading the muscularis mucosae or upper submucosa compared with the long-term outcome in a similar group of patients who underwent surgical resection. This novel treatment, EMR combined with CRT, was performed in patients with superficial esophageal carcinoma. EMR was utilized for the purpose of complete local tumor control and CRT to control regional and distant spread. PATIENTS AND METHODS Patient selection The eligibility criteria for EMR combined with CRT for patients with esophageal carcinomas invading the muscularis mucosae or upper submucosa (EMR plus CRT group) were the following: (1) refusal to undergo open surgery despite an explanation of the risk of metastasis, (2) no evidence of lymph node or distant metastasis by diagnostic imaging, (3) no concurrent illness that would increase the risk of the treatment, (4) absence of other nonesophageal advanced cancer, (5) age less than 75 years, and (6) informed consent to undergo the investigational treatment. Patients with histopathologically confirmed adenocarcinoma were excluded. The study was approved by the ethics committee of our institute, and informed consent for all procedures and for participation in the study was obtained from all patients. Before treatment, endoscopy and EUS with a highfrequency catheter US probe were performed in all patients to evaluate depth of cancer invasion. In addition, EUS with a dedicated echoendoscope, transcutaneous US, and CT also were performed in all patients to assess lymph node and distant metastasis. Lymph nodes longer than 5 mm in shortest dimension that were spherical and had distinct borders on EUS, and those longer than 10 mm in shortest dimension on CT were defined as metastatic lymph nodes.13-17 Treatment strategy was decided on the basis of these findings, as well as the condition of the patient and his/her decision as to type of treatment. Of the patients with tumors invading the muscularis mucosae or deeper, without evidence of distant metastasis, other nonesophageal advanced cancer, and increased operative risk because of concurrent illness or advanced age, who gave informed consent for open surgery, underwent esophagectomy. Among these patients, those who had no pre-operative evidence of lymph node metastasis (who were considered to have tumors suitable for either surgical resection or EMR combined with CRT) were designated the surgical resection group. The long-term outcomes for the EMR plus CRT group and the surgical resection group were prospectively compared.
Chemoradiotherapy After a 2-week interval to allow for post-EMR ulcer healing, adjuvant CRT was started. The radiation therapy field extended from the supraclavicular fossa to the esophagogastric junction, including the mediastinum. For patients with cancers that originated in the distal third of the esophagus, radiation of the supraclavicular fossa was not required and the radiation therapy field was extended to the cardia. Radiation treatments were delivered 4 days a week at 2 Gy per fraction. The total dose was 40 to 46 Gy in 20 to 23 fractions over 5 weeks. 5-fluorouracil (700 mg/m2 of body-surface area per day by 120-hour infusion) was administered on days 1 to 5. Cisplatin (15 mg/m2 of body-surface area per day intravenously) was administered with hydration on days 1 to 5. Two courses of chemotherapy were given during radiotherapy at a 3-week interval. All resection specimens of esophagus were cut into longitudinal slices measuring 2 to 5 mm in width and were embedded in paraffin. Each slice was stained with H&E and was examined microscopically. All specimens were reviewed by a single pathologist blinded to the clinical characteristics of the patients. After treatment, all patients were monitored to detect local or distant recurrence every 3 to 6 months during the first year and every 6 to 12 months thereafter. Follow-up evaluations included upper endoscopy, CT of the chest and upper abdomen, and transcutaneous US of the neck and upper abdomen. EUS also was performed for patients in the EMR plus CRT group to assess lymph node metastasis. Statistical analysis Overall survival and cause-specific survival were calculated from the date of EMR or surgical resection. Overall survival included deaths from any cause. Cause-specific survival included deaths because of esophageal carcinoma, whereas patients who died of intercurrent disease were counted withdrawn alive. Survival curves were plotted according to the Kaplan-Meier method. The significance of differences in survival was assessed by the log-rank test. Differences in frequency distributions were tested by using the chi-square test, with the Yates correction for continuity where appropriate, and quantitative data were examined with a two-tailed t test. A p value <0.05 was considered to indicate statistical significance.
RESULTS
EMR The esophageal EMR-tube (EEMR-tube) method, with endoscopic iodine staining to sharpen the contrast of the cancer margin, was used.10,11 Briefly, the EEMR-tube, 200
a translucent overtube made of silicon 60 cm in length, is introduced into the esophagus under endoscopic guidance, saline solution is injected into the submucosa beneath the lesion, a snare loop that had been passed through the outer channel of the EEMR-tube is opened widely over the lesion, the lesion is drawn inside the EEMR-tube by endoscopic suction, the snare loop is closed, and electrosurgical current is applied to resect the lesion.
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Demographic data From October 1996 to January 2002, 120 patients with squamous-cell carcinoma of the esophagus VOLUME 59, NO. 2, 2004
Esophageal squamous-cell carcinoma: EMR combined with chemoradiotherpy
underwent EMR at our two hospitals. Thirty-nine patients had histopathologically confirmed tumor invasion of the muscularis mucosae or shallow invasion of the submucosa. Four cancers (4 patients) were misdiagnosed as being confined to the lamina propria before EMR; all 4 patients subsequently underwent esophagectomy. Eight other patients refused both esophagectomy and adjuvant CRT. Eleven further patients were observed without adjuvant treatment because of concurrent illness or advanced age. The remaining 16 patients underwent EMR and CRT (EMR plus CRT group). The case of a 73-year-old-man who underwent EMR and was confirmed to have a tumor that slightly invaded the submucosa is illustrated by Figures 1 through 3. He subsequently underwent CRT. During the study period, 42 patients with esophageal carcinoma invading the muscularis mucosae or the upper third of the submucosa underwent esophagectomy with lymph node dissection at one of the two participating hospitals (Keiyukai Sapporo Hospital) (including the 4 patients who underwent esophagectomy after EMR). Three had pre-operative evidence of lymph node metastasis. The other 39 patients were considered to have tumors suitable for either surgical resection or EMR combined with CRT; these patients were designated as the surgical resection group. Characteristics of patients in the two groups are shown in Table 1. With respect to clinicopathologic factors, the differences between the two groups were insignificant. Complications and treatment toxicity No complication because of the EMR (e.g., hemorrhage, perforation) was encountered in the EMR plus CRT group. Severe hematologic toxicity (RTOG grade 3) was documented in two (12.5%) of the patients; these two patients did not undergo a second cycle of chemotherapy. Severe toxicity did not occur in the remaining 14 patients. All 16 patients completed the radiotherapy protocol. Esophagitis caused by radiotherapy occurred in all patients in the EMR plus CRT group, although the symptoms were mild and transient. No severe complication, such as esophageal fistula or life-threatening esophageal stricture, occurred in patients in the EMR plus CRT group. No death from a treatment-related complication(s) occurred in either group. Survival As of January 2003, none of the 16 patients in the EMR plus CRT group have died of recurrent VOLUME 59, NO. 2, 2004
Y Shimizu, M Kato, J Yamamoto, et al.
Figure 1. Endoscopic view of iodine-stained esophageal mucosa showing elevated type squamous-cell carcinoma with granular surface.
Figure 2. Endoscopic view of iodine-stained esophageal mucosa after EMR of lesion shown in Figure 1; no residual tumor is present.
Figure 3. Photomicrograph of squamous-cell carcinoma showing slight invasion of submucosa; complete resection of vertical margin is confirmed (H&E, orig. mag. 3200). GASTROINTESTINAL ENDOSCOPY
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Table 1. Characteristics of patients with squamous-cell carcinoma of esophagus invading muscularis mucosae or upper submucosa; no significant differences between the two groups in terms of clinicopathologic factors
Age (y):mean (SD) Range Gender (male:female) Tumor size (cm):mean SD Range Tumor location Upper Middle Lower Tumor differentiation Well Moderately Poorly
EMR + CRT group (n = 16)
Surgical resection group (n = 39)
62.5 (7.8) 52-74 15:1 2.4 (1.3) 1.4-5.2
63.3 (8.4) 43-78 36:3 2.8 (1.9) 1.5-6.0
4 9 3
8 21 10
5 10 1
11 25 3
Figure 4. Overall Kaplan-Meier survival curve for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or with shallow invasion of the submucosa who underwent EMR combined with chemoradiotherapy (EMR plus CRT group) and for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or upper third of submucosa who underwent esophagectomy (surgical resection group).
All patients in the two groups were in clinical stage T1N0M0. CRT, Chemoradiotherapy; SD, standard deviation.
esophageal carcinoma or intercurrent diseases. None have developed a local recurrence or metastasis. Two of the 39 patients in the surgical resection group died of recurrent esophageal carcinoma, including lung metastasis and liver metastasis, and two died of intercurrent diseases. The median follow-up period after treatment in the other 51 patients was 39 months (43 months, EMR plus CRT group; 38 months, surgical resection group). The minimum follow-up period was 12 months. Six patients were followed for more than 60 months. Kaplan-Meier estimates of the overall survival rates at 5 years in the EMR plus CRT and surgical resection groups were, respectively, 100% and 87.5% (Fig. 4). The cause-specific survival rates at 5 years in the EMR plus CRT and surgical resection groups were, respectively, 100% and 90.7% (Fig. 5). DISCUSSION Numerous studies of esophageal squamous-cell carcinoma have shown that lymph node metastasis occurs in 10% to 20% of patients with invasion of the muscularis mucosae or upper third of the submucosa.2,10,12,18 Such tumors, therefore, are an indication for esophagectomy with lymph node dissection. However, esophagectomy is notably invasive. According to the results of a Japanese multi-institutional study on outcomes of surgery for superficial esophageal carcinoma, pulmonary complications, recurrent nerve paralysis, and other problematic symptoms occurred in approximately 55% of patients who underwent subtotal esophagectomy, and about 3% of the patients died within 1 month of the operation.2 202
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Figure 5. Cause-specific Kaplan-Meier survival curve for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or with shallow invasion of submucosa who underwent EMR combined with chemoradiotherapy (EMR plus CRT group) and for patients with squamous-cell esophageal carcinoma invading the muscularis mucosae or upper third of submucosa who underwent esophagectomy (surgical resection group).
Esophagectomy also negatively affects the QOL for patients and can cause swallowing disturbances, aspiration pneumonia, and malnutrition. In a previous study, long-term outcome for 26 patients with esophageal carcinoma invading the muscularis mucosae or upper submucosa who underwent EMR were evaluated by us. This extended EMR group consisted of patients at increased operative risk because of concurrent illness, those who had another nonesophageal advanced cancer, those older than 75 years, and those who refused both open surgery and CRT despite an explanation of the risk of cancer metastasis. Long-term outcome in the latter group was compared with that for 44 patients with tumors of a similar stage who underwent surgical resection.19 The patients in the two groups VOLUME 59, NO. 2, 2004
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had similar cause-specific 5-year survival rates, suggesting that EMR might be an alternative choice for management of esophageal carcinoma invading the muscularis mucosae or upper submucosa. However, in addition to 4 patients who died of intercurrent diseases, two (9.1%) of the 22 patients in the extended EMR group died of regional or distant metastasis, indicating the need to consider adjuvant treatment, such as CRT, after extended EMR. Chemoradiotherapy is effective for treating squamous-cell carcinoma of the esophagus. For patients with inoperable disease, CRT can produce relatively good long-term results.7,8 Some studies have found that CRT resulted in outcomes comparable with those for surgical resection in patients with stage I or II cancer.7,20 The effects of CRT on esophageal carcinoma can be divided into local and regional or distant control. There are few data on rates of local control in patients with superficial esophageal carcinoma treated with CRT. However, Murakami et al.20 noted a 3-year local control rate of 70% in 24 patients with superficial esophageal carcinoma treated with CRT. A Japanese multi-institutional study found that the 2-year local control rate was 83.0% in 105 patients with superficial esophageal carcinoma treated with radiotherapy; 22 of the 105 patients had local recurrence within radiation fields.21 Thus, relatively good, albeit not completely satisfactory, local control can be expected in patients with superficial esophageal carcinoma treated with CRT alone. None of the 16 patients who received CRT after EMR in the present study had local recurrence or metastasis. None died of recurrent esophageal carcinoma or intercurrent diseases. Overall and causespecific survival rates in the EMR plus CRT group were equivalent to those in the surgical resection group. Furthermore, EMR restored the QOL for patients to pretreatment levels. It is our belief that the less-invasive EMR plus CRT contributed not only to QOL, but also to long-term outcome by preserving physical strength. Few severe side effects occurred in patients in the EMR with CRT group. One reason for this may be the lower dose of chemotherapy and the lower radiation beam dose. The targets of CRT in the present study were not massive tumors but micro metastatic tumors in regional and distant sites that could not be detected by diagnostic imaging. The CRT doses selected were, therefore, lower that those typically used. Another reason for the low degree of toxicity may be that the physical condition of the patients in the study was similar to that of healthy persons. Patients with esophageal carcinoma in an advanced stage, and thus in poor condition because of swallowVOLUME 59, NO. 2, 2004
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ing disturbances or metastasis, were included in many previous studies of the effectiveness of CRT for esophageal carcinoma. Other life-threatening complications, such as fistula, ulcer, and stenosis, are probably a result of necrosis and, subsequently, fibrosis of the invasive tumor, because such complications never occur in tumor-free esophageal sites. The reason for the absence of severe complications among patients in the EMR plus CRT group may be the elimination of the superficial tumor before CRT. The present study has several limitations, including that the design was not randomized assignment and the sample size was too small to eliminate a type 2 statistical error. Moreover, a study with a control group of patients who undergo CRT alone would be needed to prove that local control is better with this new treatment. Nevertheless, the results of the current study suggest that EMR combined with CRT is a safe and effective method for treatment of patients with esophageal squamous-cell carcinoma invading the muscularis mucosae or upper submucosa. The results further suggest that this treatment is equivalent, or, in view of the lower degree of invasiveness, superior to surgical resection. Further studies of EMR combined with CRT are needed to confirm these conclusions and to improve the results of this alternative approach to therapy. REFERENCES 1. Kato H, Tachimori Y, Mizobuchi S. Cervical, mediastinal, and abdominal lymph node dissection (three-field dissection) for superficial carcinoma of the thoraesophagus. Cancer 1993;72:2879-82. 2. Kodama M, Kakegawa T. Treatment of superficial cancer of the esophagus: a summary of the responses to a questionnaire on superficial cancer of the esophagus in Japan. Surgery 1998;123:432-9. 3. Herskovic A, Martz K, Al-Sarraf M, Leichman L, Brindle JS, Vaitkevicius VK, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Eng J Med 1992;326:1593-8. 4. Al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an Intergroup study. J Clin Oncol 1997; 15:277-84. 5. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Al-Sarraf M, Leichman LL, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623-7. 6. Gaspar LE, Winter K, Kocha WI, Coia LR, Herskovic A, Graham M. A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report. Cancer 2000;88:988-95. 7. Bidoli P, Bajetta E, Stani SC, De CD, Santoro A, Bonadonna G, et al. Ten-year survival with chemotherapy and GASTROINTESTINAL ENDOSCOPY
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8. 9.
10. 11.
12.
13. 14.
15.
Esophageal squamous-cell carcinoma: EMR combined with chemoradiotherpy
radiotherapy in patients with squamous cell carcinoma of the esophagus. Cancer 2002;94:352-61. Geh JI. The use of chemoradiotherapy in oesophageal cancer. Eur J Cancer 2002;38:300-13. Inoue H, Tani M, Nagai K, Kawano T, Takeshita K, Endo M, et al. Treatment of esophageal and gastric tumors. Endoscopy 1999;31:47-55. MakuuchiH.Endoscopic mucosal resectionforearly esophageal cancer: indication and techniques. Dig Endosc 1996;8:175-9. Inoue H, Fukami N, Yoshida T, Kudo S. Endoscopic mucosal resection for esophageal and gastric cancers. J Gastroenterol Hepatol 2002;17:382-8. Nagawa H, Kaizaki S, Seto Y, Tominaga O, Muto T. The relationship of macroscopic shape of superficial esophageal carcinoma to depth of invasion and regional lymph node metastasis. Cancer 1995;75:1061-4. Dittler HJ, Siewert JR. Role of endoscopic ultrasonography in esophageal carcinoma. Endoscopy 1993;25:156-61. Murata Y, Muroi M, Yoshida M. Endoscopic ultrasonography in the diagnosis of esophageal carcinoma. Surg Endosc 1987; 1:11-6. Shimizu Y, Tsukagoshi H, Oohara M, Hosokawa M, Fujita M, Asaka M, et al. Endoscopic ultrasonography for the detection of lymph node metastasis in superficial esophageal carcinoma. Dig Endosc 1997;9:178-82.
16. Koch J, Halvorsen RA Jr. Staging of esophageal cancer: computed tomography, magnetic resonance, and endoscopic ultrasound. Semin Roentgenol 1994;29:364-72. 17. Greenberg J, Durkin M, Drunen MV, Aranha GV. Computed tomography or endoscopic ultrasonography in preoperative staging of gastric and esophageal tumors. Surgery 1994; 116:696-702. 18. Araki K, Ohno S, Egashira A, Saeki H, Kawaguchi H, Sugimachi K. Pathologic features of superficial esophageal squamous cell carcinoma with lymph node and distal metastasis. Cancer 2002;94:570-5. 19. Shimizu Y, Tsukagoshi H, Fujita M, Hosokawa M, Kato M, Asaka M. Long-term outcome after endoscopic mucosal resection in patients with esophageal squamous cell carcinoma invading the muscularis mucosae or deeper. Gastrointest Endosc 2002;56:387-90. 20. Murakami M, Kuroda Y, Nakajima T, Okamoto Y, Mizowaki T, Takeda H, et al. Comparison between chemoradiation protocol intended for organ preservation and conventional surgery for clinical T1-T2 esophageal carcinoma. Int J Radiat Oncol Biol Phys 1999;45:277-84. 21. Okawa T, Tanaka M, Kita-Okawa M, Nishio M, Shirato H, Miyaji N, et al. Superficial esophageal cancer: multicenter analysis of results of definitive radiation therapy in Japan. Radiology 1995;196:271-4.
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VOLUME 59, NO. 2, 2004
Background: Esophagectomy or chemoradiotherapy (CRT) are the procedures of choice for patients with superficial esophageal squamous-cell carcinoma. However, esophagectomy is highly invasive, and CRT is associated with the risk of local failure. A study was conducted of a novel treatment, EMR combined with CRT, for patients with superficial esophageal carcinoma. EMR was performed for the purpose of complete local tumor control and chemoradiotherapy was performed for regional and distant control. Methods: EMR combined with CRT was performed for patients with esophageal carcinoma invading the muscularis mucosae or upper submucosa who refused esophagectomy. The planned treatment after EMR was 40 to 46 Gy of external beam radiation to the mediastinum, including the supraclavicular fossa or cardia. Chemotherapy was given during weeks 1 and 5 (5-fluorouracil, 700 mg/m2 per 24 hours in a 120-hour infusion, and cisplatin 15 mg/m2 per day intravenously on days 1 to 5). Results: During the study period, 16 patients underwent EMR combined with CRT (EMR plus CRT group) and 39 patients with similar stage cancer underwent esophagectomy (surgical resection group). None of the patients in the EMR plus CRT group have had local recurrence or metastasis. Overall survival rates at 5 years in the EMR plus CRT and surgical resection groups were estimated to be, respectively, 100% and 87.5%. Conclusions: Although this study was not randomized, the results suggest that EMR combined with CRT is a safe and effective method for treating patients with superficial esophageal carcinoma. The results were equivalent or, in view of the lower degree of invasiveness, superior to surgical resection. (Gastrointest Endosc 2004;59:199-204.)
Because of the development of endoscopic methods of diagnosis, the frequency of superficial esophageal carcinoma, i.e., esophageal carcinoma that has not invaded beyond the submucosa (T1; International Union Against Cancer, 1997) has increased relative to the frequency of esophageal squamous-cell carcinoma of all stages. Subtotal esophagectomy with lymph node dissection is the treatment of choice for patients with superficial esophageal carcinoma invading the muscularis mucosae or deeper histologic layers because lymph node metastasis often occurs with such tumors.1,2 However, esophagectomy is highly invasive and associated with increased morReceived June 16, 2003. For revision September 4, 2003. Accepted November 4, 2003. Current affiliations: Division of Endoscopy, Hokkaido University Medical Hospital, Sapporo, Japan, Department of Internal Medicine, Department of Pathology, Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan, Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan. Reprint requests: Yuichi Shimizu, MD, Division of Endoscopy, Hokkaido University Medical Hospital, Kita 15 jo Nishi 7, chome, Kitaku, Sapporo 060-8638, Japan. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(03)02688-9 VOLUME 59, NO. 2, 2004
bidity and mortality.2 Chemoradiotherapy (CRT) is an alternative treatment for patients with superficial esophageal carcinoma. Many studies have demonstrated the effectiveness of CRT for patients with esophageal squamous-cell carcinoma.3-8 The Radiation Therapy Oncology Group in North America (RTOG) reported a complete response rate of 74% in 49 patients with stage II-III esophageal carcinoma who underwent CRT.6 Nevertheless, local failure often occurs in patients who have undergone CRT, and local tumor control remains the biggest problem. In the RTOG study, the final local cancer persistence or recurrence rate was 63%.6 EMR increasingly is being used to treat early stage esophageal carcinoma because it is minimally invasive and benefits patients in terms of quality of life (QOL).9-12 EMR currently is recommended for tumors confined to the lamina propria of the mucosa, which are known to have no risk of lymph node metastasis.2,9-12 However, it is possible to completely remove tumors invading the upper third to upper half of the submucosa by using EMR techniques.9,11 Because of the completeness of local tumor control, EMR is regarded by us as the best procedure for patients with superficial carcinoma, except for those with tumors invading the deep submucosa. GASTROINTESTINAL ENDOSCOPY
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Y Shimizu, M Kato, J Yamamoto, et al.
Esophageal squamous-cell carcinoma: EMR combined with chemoradiotherpy
This study prospectively evaluates the long-term outcome after EMR combined with CRT in patients with squamous-cell carcinoma of the esophagus invading the muscularis mucosae or upper submucosa compared with the long-term outcome in a similar group of patients who underwent surgical resection. This novel treatment, EMR combined with CRT, was performed in patients with superficial esophageal carcinoma. EMR was utilized for the purpose of complete local tumor control and CRT to control regional and distant spread. PATIENTS AND METHODS Patient selection The eligibility criteria for EMR combined with CRT for patients with esophageal carcinomas invading the muscularis mucosae or upper submucosa (EMR plus CRT group) were the following: (1) refusal to undergo open surgery despite an explanation of the risk of metastasis, (2) no evidence of lymph node or distant metastasis by diagnostic imaging, (3) no concurrent illness that would increase the risk of the treatment, (4) absence of other nonesophageal advanced cancer, (5) age less than 75 years, and (6) informed consent to undergo the investigational treatment. Patients with histopathologically confirmed adenocarcinoma were excluded. The study was approved by the ethics committee of our institute, and informed consent for all procedures and for participation in the study was obtained from all patients. Before treatment, endoscopy and EUS with a highfrequency catheter US probe were performed in all patients to evaluate depth of cancer invasion. In addition, EUS with a dedicated echoendoscope, transcutaneous US, and CT also were performed in all patients to assess lymph node and distant metastasis. Lymph nodes longer than 5 mm in shortest dimension that were spherical and had distinct borders on EUS, and those longer than 10 mm in shortest dimension on CT were defined as metastatic lymph nodes.13-17 Treatment strategy was decided on the basis of these findings, as well as the condition of the patient and his/her decision as to type of treatment. Of the patients with tumors invading the muscularis mucosae or deeper, without evidence of distant metastasis, other nonesophageal advanced cancer, and increased operative risk because of concurrent illness or advanced age, who gave informed consent for open surgery, underwent esophagectomy. Among these patients, those who had no pre-operative evidence of lymph node metastasis (who were considered to have tumors suitable for either surgical resection or EMR combined with CRT) were designated the surgical resection group. The long-term outcomes for the EMR plus CRT group and the surgical resection group were prospectively compared.
Chemoradiotherapy After a 2-week interval to allow for post-EMR ulcer healing, adjuvant CRT was started. The radiation therapy field extended from the supraclavicular fossa to the esophagogastric junction, including the mediastinum. For patients with cancers that originated in the distal third of the esophagus, radiation of the supraclavicular fossa was not required and the radiation therapy field was extended to the cardia. Radiation treatments were delivered 4 days a week at 2 Gy per fraction. The total dose was 40 to 46 Gy in 20 to 23 fractions over 5 weeks. 5-fluorouracil (700 mg/m2 of body-surface area per day by 120-hour infusion) was administered on days 1 to 5. Cisplatin (15 mg/m2 of body-surface area per day intravenously) was administered with hydration on days 1 to 5. Two courses of chemotherapy were given during radiotherapy at a 3-week interval. All resection specimens of esophagus were cut into longitudinal slices measuring 2 to 5 mm in width and were embedded in paraffin. Each slice was stained with H&E and was examined microscopically. All specimens were reviewed by a single pathologist blinded to the clinical characteristics of the patients. After treatment, all patients were monitored to detect local or distant recurrence every 3 to 6 months during the first year and every 6 to 12 months thereafter. Follow-up evaluations included upper endoscopy, CT of the chest and upper abdomen, and transcutaneous US of the neck and upper abdomen. EUS also was performed for patients in the EMR plus CRT group to assess lymph node metastasis. Statistical analysis Overall survival and cause-specific survival were calculated from the date of EMR or surgical resection. Overall survival included deaths from any cause. Cause-specific survival included deaths because of esophageal carcinoma, whereas patients who died of intercurrent disease were counted withdrawn alive. Survival curves were plotted according to the Kaplan-Meier method. The significance of differences in survival was assessed by the log-rank test. Differences in frequency distributions were tested by using the chi-square test, with the Yates correction for continuity where appropriate, and quantitative data were examined with a two-tailed t test. A p value <0.05 was considered to indicate statistical significance.
RESULTS
EMR The esophageal EMR-tube (EEMR-tube) method, with endoscopic iodine staining to sharpen the contrast of the cancer margin, was used.10,11 Briefly, the EEMR-tube, 200
a translucent overtube made of silicon 60 cm in length, is introduced into the esophagus under endoscopic guidance, saline solution is injected into the submucosa beneath the lesion, a snare loop that had been passed through the outer channel of the EEMR-tube is opened widely over the lesion, the lesion is drawn inside the EEMR-tube by endoscopic suction, the snare loop is closed, and electrosurgical current is applied to resect the lesion.
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Demographic data From October 1996 to January 2002, 120 patients with squamous-cell carcinoma of the esophagus VOLUME 59, NO. 2, 2004
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underwent EMR at our two hospitals. Thirty-nine patients had histopathologically confirmed tumor invasion of the muscularis mucosae or shallow invasion of the submucosa. Four cancers (4 patients) were misdiagnosed as being confined to the lamina propria before EMR; all 4 patients subsequently underwent esophagectomy. Eight other patients refused both esophagectomy and adjuvant CRT. Eleven further patients were observed without adjuvant treatment because of concurrent illness or advanced age. The remaining 16 patients underwent EMR and CRT (EMR plus CRT group). The case of a 73-year-old-man who underwent EMR and was confirmed to have a tumor that slightly invaded the submucosa is illustrated by Figures 1 through 3. He subsequently underwent CRT. During the study period, 42 patients with esophageal carcinoma invading the muscularis mucosae or the upper third of the submucosa underwent esophagectomy with lymph node dissection at one of the two participating hospitals (Keiyukai Sapporo Hospital) (including the 4 patients who underwent esophagectomy after EMR). Three had pre-operative evidence of lymph node metastasis. The other 39 patients were considered to have tumors suitable for either surgical resection or EMR combined with CRT; these patients were designated as the surgical resection group. Characteristics of patients in the two groups are shown in Table 1. With respect to clinicopathologic factors, the differences between the two groups were insignificant. Complications and treatment toxicity No complication because of the EMR (e.g., hemorrhage, perforation) was encountered in the EMR plus CRT group. Severe hematologic toxicity (RTOG grade 3) was documented in two (12.5%) of the patients; these two patients did not undergo a second cycle of chemotherapy. Severe toxicity did not occur in the remaining 14 patients. All 16 patients completed the radiotherapy protocol. Esophagitis caused by radiotherapy occurred in all patients in the EMR plus CRT group, although the symptoms were mild and transient. No severe complication, such as esophageal fistula or life-threatening esophageal stricture, occurred in patients in the EMR plus CRT group. No death from a treatment-related complication(s) occurred in either group. Survival As of January 2003, none of the 16 patients in the EMR plus CRT group have died of recurrent VOLUME 59, NO. 2, 2004
Y Shimizu, M Kato, J Yamamoto, et al.
Figure 1. Endoscopic view of iodine-stained esophageal mucosa showing elevated type squamous-cell carcinoma with granular surface.
Figure 2. Endoscopic view of iodine-stained esophageal mucosa after EMR of lesion shown in Figure 1; no residual tumor is present.
Figure 3. Photomicrograph of squamous-cell carcinoma showing slight invasion of submucosa; complete resection of vertical margin is confirmed (H&E, orig. mag. 3200). GASTROINTESTINAL ENDOSCOPY
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Table 1. Characteristics of patients with squamous-cell carcinoma of esophagus invading muscularis mucosae or upper submucosa; no significant differences between the two groups in terms of clinicopathologic factors
Age (y):mean (SD) Range Gender (male:female) Tumor size (cm):mean SD Range Tumor location Upper Middle Lower Tumor differentiation Well Moderately Poorly
EMR + CRT group (n = 16)
Surgical resection group (n = 39)
62.5 (7.8) 52-74 15:1 2.4 (1.3) 1.4-5.2
63.3 (8.4) 43-78 36:3 2.8 (1.9) 1.5-6.0
4 9 3
8 21 10
5 10 1
11 25 3
Figure 4. Overall Kaplan-Meier survival curve for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or with shallow invasion of the submucosa who underwent EMR combined with chemoradiotherapy (EMR plus CRT group) and for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or upper third of submucosa who underwent esophagectomy (surgical resection group).
All patients in the two groups were in clinical stage T1N0M0. CRT, Chemoradiotherapy; SD, standard deviation.
esophageal carcinoma or intercurrent diseases. None have developed a local recurrence or metastasis. Two of the 39 patients in the surgical resection group died of recurrent esophageal carcinoma, including lung metastasis and liver metastasis, and two died of intercurrent diseases. The median follow-up period after treatment in the other 51 patients was 39 months (43 months, EMR plus CRT group; 38 months, surgical resection group). The minimum follow-up period was 12 months. Six patients were followed for more than 60 months. Kaplan-Meier estimates of the overall survival rates at 5 years in the EMR plus CRT and surgical resection groups were, respectively, 100% and 87.5% (Fig. 4). The cause-specific survival rates at 5 years in the EMR plus CRT and surgical resection groups were, respectively, 100% and 90.7% (Fig. 5). DISCUSSION Numerous studies of esophageal squamous-cell carcinoma have shown that lymph node metastasis occurs in 10% to 20% of patients with invasion of the muscularis mucosae or upper third of the submucosa.2,10,12,18 Such tumors, therefore, are an indication for esophagectomy with lymph node dissection. However, esophagectomy is notably invasive. According to the results of a Japanese multi-institutional study on outcomes of surgery for superficial esophageal carcinoma, pulmonary complications, recurrent nerve paralysis, and other problematic symptoms occurred in approximately 55% of patients who underwent subtotal esophagectomy, and about 3% of the patients died within 1 month of the operation.2 202
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Figure 5. Cause-specific Kaplan-Meier survival curve for patients with squamous-cell esophageal carcinoma invading muscularis mucosae or with shallow invasion of submucosa who underwent EMR combined with chemoradiotherapy (EMR plus CRT group) and for patients with squamous-cell esophageal carcinoma invading the muscularis mucosae or upper third of submucosa who underwent esophagectomy (surgical resection group).
Esophagectomy also negatively affects the QOL for patients and can cause swallowing disturbances, aspiration pneumonia, and malnutrition. In a previous study, long-term outcome for 26 patients with esophageal carcinoma invading the muscularis mucosae or upper submucosa who underwent EMR were evaluated by us. This extended EMR group consisted of patients at increased operative risk because of concurrent illness, those who had another nonesophageal advanced cancer, those older than 75 years, and those who refused both open surgery and CRT despite an explanation of the risk of cancer metastasis. Long-term outcome in the latter group was compared with that for 44 patients with tumors of a similar stage who underwent surgical resection.19 The patients in the two groups VOLUME 59, NO. 2, 2004
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had similar cause-specific 5-year survival rates, suggesting that EMR might be an alternative choice for management of esophageal carcinoma invading the muscularis mucosae or upper submucosa. However, in addition to 4 patients who died of intercurrent diseases, two (9.1%) of the 22 patients in the extended EMR group died of regional or distant metastasis, indicating the need to consider adjuvant treatment, such as CRT, after extended EMR. Chemoradiotherapy is effective for treating squamous-cell carcinoma of the esophagus. For patients with inoperable disease, CRT can produce relatively good long-term results.7,8 Some studies have found that CRT resulted in outcomes comparable with those for surgical resection in patients with stage I or II cancer.7,20 The effects of CRT on esophageal carcinoma can be divided into local and regional or distant control. There are few data on rates of local control in patients with superficial esophageal carcinoma treated with CRT. However, Murakami et al.20 noted a 3-year local control rate of 70% in 24 patients with superficial esophageal carcinoma treated with CRT. A Japanese multi-institutional study found that the 2-year local control rate was 83.0% in 105 patients with superficial esophageal carcinoma treated with radiotherapy; 22 of the 105 patients had local recurrence within radiation fields.21 Thus, relatively good, albeit not completely satisfactory, local control can be expected in patients with superficial esophageal carcinoma treated with CRT alone. None of the 16 patients who received CRT after EMR in the present study had local recurrence or metastasis. None died of recurrent esophageal carcinoma or intercurrent diseases. Overall and causespecific survival rates in the EMR plus CRT group were equivalent to those in the surgical resection group. Furthermore, EMR restored the QOL for patients to pretreatment levels. It is our belief that the less-invasive EMR plus CRT contributed not only to QOL, but also to long-term outcome by preserving physical strength. Few severe side effects occurred in patients in the EMR with CRT group. One reason for this may be the lower dose of chemotherapy and the lower radiation beam dose. The targets of CRT in the present study were not massive tumors but micro metastatic tumors in regional and distant sites that could not be detected by diagnostic imaging. The CRT doses selected were, therefore, lower that those typically used. Another reason for the low degree of toxicity may be that the physical condition of the patients in the study was similar to that of healthy persons. Patients with esophageal carcinoma in an advanced stage, and thus in poor condition because of swallowVOLUME 59, NO. 2, 2004
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ing disturbances or metastasis, were included in many previous studies of the effectiveness of CRT for esophageal carcinoma. Other life-threatening complications, such as fistula, ulcer, and stenosis, are probably a result of necrosis and, subsequently, fibrosis of the invasive tumor, because such complications never occur in tumor-free esophageal sites. The reason for the absence of severe complications among patients in the EMR plus CRT group may be the elimination of the superficial tumor before CRT. The present study has several limitations, including that the design was not randomized assignment and the sample size was too small to eliminate a type 2 statistical error. Moreover, a study with a control group of patients who undergo CRT alone would be needed to prove that local control is better with this new treatment. Nevertheless, the results of the current study suggest that EMR combined with CRT is a safe and effective method for treatment of patients with esophageal squamous-cell carcinoma invading the muscularis mucosae or upper submucosa. The results further suggest that this treatment is equivalent, or, in view of the lower degree of invasiveness, superior to surgical resection. Further studies of EMR combined with CRT are needed to confirm these conclusions and to improve the results of this alternative approach to therapy. REFERENCES 1. Kato H, Tachimori Y, Mizobuchi S. Cervical, mediastinal, and abdominal lymph node dissection (three-field dissection) for superficial carcinoma of the thoraesophagus. Cancer 1993;72:2879-82. 2. Kodama M, Kakegawa T. Treatment of superficial cancer of the esophagus: a summary of the responses to a questionnaire on superficial cancer of the esophagus in Japan. Surgery 1998;123:432-9. 3. Herskovic A, Martz K, Al-Sarraf M, Leichman L, Brindle JS, Vaitkevicius VK, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Eng J Med 1992;326:1593-8. 4. Al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an Intergroup study. J Clin Oncol 1997; 15:277-84. 5. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Al-Sarraf M, Leichman LL, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623-7. 6. Gaspar LE, Winter K, Kocha WI, Coia LR, Herskovic A, Graham M. A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report. Cancer 2000;88:988-95. 7. Bidoli P, Bajetta E, Stani SC, De CD, Santoro A, Bonadonna G, et al. Ten-year survival with chemotherapy and GASTROINTESTINAL ENDOSCOPY
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8. 9.
10. 11.
12.
13. 14.
15.
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radiotherapy in patients with squamous cell carcinoma of the esophagus. Cancer 2002;94:352-61. Geh JI. The use of chemoradiotherapy in oesophageal cancer. Eur J Cancer 2002;38:300-13. Inoue H, Tani M, Nagai K, Kawano T, Takeshita K, Endo M, et al. Treatment of esophageal and gastric tumors. Endoscopy 1999;31:47-55. MakuuchiH.Endoscopic mucosal resectionforearly esophageal cancer: indication and techniques. Dig Endosc 1996;8:175-9. Inoue H, Fukami N, Yoshida T, Kudo S. Endoscopic mucosal resection for esophageal and gastric cancers. J Gastroenterol Hepatol 2002;17:382-8. Nagawa H, Kaizaki S, Seto Y, Tominaga O, Muto T. The relationship of macroscopic shape of superficial esophageal carcinoma to depth of invasion and regional lymph node metastasis. Cancer 1995;75:1061-4. Dittler HJ, Siewert JR. Role of endoscopic ultrasonography in esophageal carcinoma. Endoscopy 1993;25:156-61. Murata Y, Muroi M, Yoshida M. Endoscopic ultrasonography in the diagnosis of esophageal carcinoma. Surg Endosc 1987; 1:11-6. Shimizu Y, Tsukagoshi H, Oohara M, Hosokawa M, Fujita M, Asaka M, et al. Endoscopic ultrasonography for the detection of lymph node metastasis in superficial esophageal carcinoma. Dig Endosc 1997;9:178-82.
16. Koch J, Halvorsen RA Jr. Staging of esophageal cancer: computed tomography, magnetic resonance, and endoscopic ultrasound. Semin Roentgenol 1994;29:364-72. 17. Greenberg J, Durkin M, Drunen MV, Aranha GV. Computed tomography or endoscopic ultrasonography in preoperative staging of gastric and esophageal tumors. Surgery 1994; 116:696-702. 18. Araki K, Ohno S, Egashira A, Saeki H, Kawaguchi H, Sugimachi K. Pathologic features of superficial esophageal squamous cell carcinoma with lymph node and distal metastasis. Cancer 2002;94:570-5. 19. Shimizu Y, Tsukagoshi H, Fujita M, Hosokawa M, Kato M, Asaka M. Long-term outcome after endoscopic mucosal resection in patients with esophageal squamous cell carcinoma invading the muscularis mucosae or deeper. Gastrointest Endosc 2002;56:387-90. 20. Murakami M, Kuroda Y, Nakajima T, Okamoto Y, Mizowaki T, Takeda H, et al. Comparison between chemoradiation protocol intended for organ preservation and conventional surgery for clinical T1-T2 esophageal carcinoma. Int J Radiat Oncol Biol Phys 1999;45:277-84. 21. Okawa T, Tanaka M, Kita-Okawa M, Nishio M, Shirato H, Miyaji N, et al. Superficial esophageal cancer: multicenter analysis of results of definitive radiation therapy in Japan. Radiology 1995;196:271-4.
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